The present invention is related to novel compounds having affinity to one or more GABAB receptors, as well as to their pharmaceutically acceptable salts, solvates and stereoisomers. The invention is also related to processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
Gastro-oesophageal reflux disease (GORD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or at reducing oesophageal acid exposure by enhancing oesophageal clearance, lower oesophageal sphincter tone and gastric emptying. The major mechanism behind reflux has earlier been considered to depend on a hypotonic lower oesophageal sphincter. However recent research (e.g. Holloway and Dent (1990) Gastroenterol. Clin. N. Amer. 19, 517-535) has shown that most reflux episodes occur during transient lower oesophageal sphincter relaxations, hereinafter referred to as TLOSR, i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GORD.
Consequently, there is a need for compounds which reduce the incidence of TLOSR and thereby prevent reflux.
Pharmaceutical compositions comprising a local anaesthetic, adapted to inhibit relaxation of the lower oesophageal sphicter are disclosed in WO 87/04077 and in U.S. Pat. No. 5,036,057. Recently GABAB-receptor agonists have been shown to inhibit TLOSR which is disclosed in WO 98/11885.
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABAA and GABAB receptor subtypes. GABAB receptors belong to the superfamily of G-protein coupled receptors. GABAB receptor agonists are being described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents. GABAB receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680) and recently, as mentioned above, in the inhibition of TLOSR (WO 98/11885).
The most studied GABAB receptor agonist is baclofen (4-amino-3-(chlorophenyl)butanoic is acid) disclosed in the Swiss patent No. CH 449, 046. Baclofen has for several years been used as an antispastic agent. EP 0356128 describes the use of the specific compound (3-aminopropyl)methylphosphinic acid, as a potent GABAB receptor agonist, in therapy. EP 0181833 discloses substituted 3-aminopropylphosphinic acids which are found to have very high affinities towards GABAB receptor sites. In analogy to baclofen, the compounds can be used as for instance muscle relaxants. EP 0399949 discloses derivatives of (3-aminopropyl)methylphosphinic acid which are described as potent GABAB receptor agonists. These compounds are stated to be useful as muscle relaxants. EP 0463969 and FR 2722192 are both applications related to 4-aminobutanoic acid derivatives having different heterocyclic substituents at the 3-carbon of the butyl chain. Structure-activity relationships of several phosphinic acid analogues with respect to their affinities to the GABAB receptor as well as their muscle relaxant effect are discussed in J. Med. Chem. (1995), 38, 3297-3312. The conclusion in said article is that considerably stronger muscle relaxation could be achieved with the (S)-enantiomer of 3-amino-2-hydroxypropylmethylphosphinic acid than with baclofen and without the occurrence of unwanted CNS effects.
In literature the phosphinic acids having a hydrogen atom attached to phosphorous also are named phosphonous acids. These are two names for the same compounds and both names can be used. However, we have chosen to use the name phosphinic acids for the compounds according to the present invention.
The present invention provides novel compounds of the formula I 
wherein
R1 represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;
R2 represents hydroxy, mercapto, halogen, or an oxo group;
R3 represents hydrogen or lower alkyl (optionally substituted with hydroxy, mercapto, lower alkoxy, lower thioalkoxy or aryl);
R4 represents hydrogen, lower alkyl (optionally substituted with aryl), or aryl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof,
with the exceptions of:
i) the racemate of (3-amino-2-hydroxypropyl)phosphinic acid, and
ii) (2R/S, 3R)-(3-amino-2-hydroxybutyl)phosphinic acid.
In a preferred embodiment
R1 represents hydrogen, a lower alkyl or halogen;
R2 represents halogen, hydroxy or an oxo group;
R3 represents hydrogen; and
R4 represents hydrogen;
with the exception of the racemate of (3-amino-2-hydroxypropyl)phosphinic acid.
Even more preferred compounds are (3-amino-2-fluoropropyl)phosphinic acid, (2R)-(3-amino-2-fluoropropyl)phosphinic acid, (2S)-(3-amino-2-fluoropropyl)phosphinic acid, (3-amino-2-fluoro-1-methylpropyl)phosphinic acid, (3-amino-2-oxopropyl)phosphinic acid, (2S)-(3-amino-2-hydroxypropyl)phosphinic acid, (2R)-(3-amino-2-hydroxypropyl)phosphinic acid and (3-amino-1-fluoro-2-hydroxypropyl)phosphinic acid.
Within the scope of the invention, it is to be understood that when R2 is an oxo group the bond between R2 and the carbon is a double bond.
Within the scope of the invention, it is to be understood by xe2x80x9clowerxe2x80x9d radicals and compounds, for example, those having up to and including 7, especially up to and including 4, carbon atoms. Also the general terms have the following meanings:
Lower alkyl is, for example, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
Lower alkoxy is, for example, C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
Halogen is halogen of atomic number up to and including 35, such as fluorine or chlorine and less preferred bromine.
The compounds according to formula I of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines. The salts may be prepared by conventional methods.
When one or more stereocentre is present in the molecule, the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer. The compounds can also be in the form of solvates, e.g. hydrates.
All of the compounds according to the formula I can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux disease. The said inhibition of TLOSR also implies that the said compounds of formula I can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient. Furthermore the novel compounds can be used for the treatment of GORD-related or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception.
As opposed to what is stated in prior art, (J. Med. Chem. (1995) 3297-3312 and The GABA Receptors; Second Edition, Edited by S. J Enna and Norman Bowery, Humana Press (1997) especially p. 281-282), the compounds according to the invention have surprisingly high metabolic stability in spite of the presence of a Pxe2x80x94H bond. The compounds also possess a surprisingly high therapeutic index.
The compounds according to formula I of the present invention may be prepared by one of the following methods.
A) A Compound of Formula II 
in which R1 and R3 are as defined above in formula I, X is hydrogen or a protecting group such as xe2x80x94CCH3(OCH2CH3)2, Z is a protecting group such as t-butyloxycarbonyl and Y is hydrogen or a protecting group such as lower alkyl, which compound of formula II may have been synthesized by a condensation reaction according to Scheme 1 employing an appropriate N-protected amino acid ester in which R3 is as defined above, W is a protecting group such as lower alkyl and Z is as defined in formula II, and a suitable protected phosphinic acid derivative in which R1 is as defined above in formula I, X and Y are as defined in formula II, and a base such as lithium diisopropylamide, 
is
a) optionally converted by an N-alkylation reaction in order to introduce R4 if R4 is desired to be not equal to hydrogen, and thereafter a hydrolytic reaction to obtain a compound of formula III 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound III into another chemical compound of the formula III and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula III and/or into another salt and/or convert a resulting free compound of the formula III into a salt to correspond to the above definition, or
b) converted by a reductive reaction, optionally an N-alkylation reaction if R4 is desired to be not equal to hydrogen, and finally a hydrolytic reaction to obtain a compound of formula IV 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound IV into another chemical compound of the formula IV and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula IV and/or into another salt and/or convert a resulting free compound of the formula IV into a salt to correspond to the above definition, or
c) converted by a reductive reaction followed by a deoxohalogenation reaction, optionally an N-alkylation reaction in order to introduce R4 if R4 is desired to be not equal to hydrogen, and finally a hydrolytic reaction to obtain a compound of formula V 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I and Halo is a halogen atom, and optionally convert the above resulting compound V into another chemical compound of the formula V and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula V and/or into another salt and/or convert a resulting free compound of the formula V into a salt to correspond to the above definition; or
B) A Compound of Formula VI 
in which R1, and R3 are as defined above in formula I, X is hydrogen or a protecting group such as xe2x80x94CCH3(OCH2CH3)2, T is a group that can be converted to axe2x80x94NH2 group, and Y is hydrogen or a protecting group such as lower alkyl, which compound of formula VI may have been synthesized by a condensation reaction according to Scheme 2 employing an 2,3-epoxypropyl derivative, such as an appropriate N-protected 2,3-epoxypropylamine derivative or an epichlorohydrin derivative, in which R1 and R3 is as defined above in formula I, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula VI, and a Lewis acid such as anhydrous ZnCl2, 
is
a) converted by a reaction where the trimethylsilyl group is replaced by a hydrogen atom, a reaction where the T group as defined in formula VI is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula IV 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound IV into another chemical compound of the formula IV and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula IV and/or into another salt and/or convert a resulting free compound of the formula IV into a salt to correspond to the above definition, or
b) converted by a reaction where the trimethylsilyl group is replaced by hydrogen, an oxidative reaction, a reaction where the T group as defined in formula VI is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula III 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound III into another chemical compound of the formula III and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula III and/or into another salt and/or convert a resulting free compound of the formula III into a salt to correspond to the above definition, or
c) converted by a reaction where the trimethylsilyl group is replaced by hydrogen, a deoxohalogenation reaction, a reaction where the T group as defined in formula VI is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula V 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I, and Halo is a halogen atom, and optionally convert the above resulting compound V into another chemical compound of the formula V and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula V and/or into another salt and/or convert a resulting free compound of the formula V into a salt to correspond to the above definition; or
C) A Compound of Formula VII 
in which R1 is as defined above in formula I, X is hydrogen or a protecting group such as xe2x80x94CCH3 (OCH2CH3)2, U is an electron-withdrawing group, such as for instance xe2x80x94CN or xe2x80x94CO2Et which can be converted to a xe2x80x94CH2NH2 group, and Y is hydrogen or a protecting group such as lower alkyl, and Halo is a halogen atom, which compound of formula VII may have been synthesized by an addition reaction according to Scheme 3 employing an unsaturated compound in which R1 is as defined above in formula I, U and halo are as defined in formula VII, and a suitable protected phosphinic acid derivative activated by O-silylation, in which X and Y are as defined in formula VII, 
is converted by a reaction where the U group is being converted to xe2x80x94NHR4 wherein R4 is a defined above in formula I, and a hydrolytic reaction to obtain a compound of formula VIII 
wherein R1 and R4 are as defined above in formula I and Halo is a halogen atom, and optionally convert the above resulting compound viii into another chemical compound of the formula VIII and/or separate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VIII and/or into another salt and/or convert a resulting free compound of the formula VIII into a salt to correspond to the above definition; or
D) A Compound of Formula IX Optionally as an Individual Stereo Isomer 
in which R1, R3 and R4 are as defined in formula I, Z is a protecting group such as t-butyloxycarbonyl and Halo is a halogen atom, which compound of formula IX may have been synthesized by a substitution reaction according to Scheme 4 employing an electrophilic compound in which R1, R3 and R4 are as defined above, L is a leaving group such as iodo, Z and Halo are as defined above, and phosphinic acid activated by O-silylation, 
is converted by a hydrolytic reaction to a compound of formula V 
wherein R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound V into another chemical compound of the formula V and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula V and/or into another salt and/or convert a resulting free compound of the formula V into a salt to correspond to the above definition; or
E) A Compound of Formula XI 
in which R1, R3 and R4 are as defined above in formula I, X is hydrogen or a protecting group such as xe2x80x94CCH3(OCH2CH3)2, and Y is hydrogen or a protecting group such as lower alkyl, which compound of formula XI may have been synthesized by an addition reaction according to Scheme 4 treating an unsaturated phosphinic acid derivative, in which R1, R3 and R4 are as defined in above in formula I, with H2S, a mercaptide ion (HSxe2x88x92) or a protected mercapto compound such as benzyl thiol in which case the protective group thereafter is removed 
is converted by a hydrolytic reaction to obtain a compound of formula XII, 
in which R1, R3 and R4 are as defined above in formula I, and optionally convert the above resulting compound XII into another chemical compound of the formula XII and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula XII and/or into another salt and/or convert a resulting free compound of the formula XII into a salt to correspond to the above definition.
The invention is described more in detail by the following non-limiting examples